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US 6,284,778 B1Granted
Methods and compositions for stimulating neurite growth
AssigneeVertex Pharmaceuticals Incorporated
InventorsRobert E. Zelle, Michael Su
Life of this patent
Estimating the term…
Abstract
The present invention relates to methods and pharmaceutical compositions for stimulating the growth of neurites in nerve cells. The compositions comprise a neurotrophic amount of a compound and a neurotrophic factor, such as nerve growth factor (NGF). The methods comprise treating nerve cells with the above compositions or compositions comprising the compound without a neurotropic factor. The methods of this invention can be used to promote repair of neuronal damage caused by disease or physical trauma.
Claims7
A pharmaceutically acceptable composition comprising:
- a) a neurotrophic amount of a compound having the formula (I):
- and pharmaceutically acceptable derivatives thereof, wherein:
- B and D are independently:
- hydrogen, Ar, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl substituted (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;
- R1 is (C5-C7) cycloalkyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkyl substituted (C3-C6) straight or branched alkenyl or alkynyl, (C5-C7) cycloalkenyl substituted (C1-C6) straight or branched alkyl, (C5-C7) cycloalkenyl substituted (C3-C6) straight or branched alkenyl or alkynyl, Ar-substituted (C1-C6) straight or branched alkyl, Ar-substituted (C3-C6) straight or branched alkenyl or alkynyl;
- wherein any one of the CH2 groups of said alkyl chains in R1, B and D is optionally replaced by O, S, SO, SO2 or NR;
- wherein R is hydrogen, (C1-C6) straight or branched alkyl, (C3-C4) straight or branched alkenyl or alkynyl, or (C1-C4) bridging-alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said alkyl chain to form a ring, and wherein said ring is optionally fused to Ar;
- wherein each Ar is independently selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H -indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
- and
- wherein each Ar is optionally and independently substituted with one to three substituents independently selected from hydrogen, halogen, hydroxyl, nitro, —SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6) straight or branched alkyl, O—((C1-C6) straight or branched alkyl), O-benzyl, O-phenyl, 1,2-methylenedioxy, —NR5R6, carboxyl, N—(C1-C6 straight or branched alkyl or C3-C5 straight or branched alkenyl) carboxamide, N,N-di-((C1-C6) straight or branched alkyl or (C3-C5) straight or branched alkenyl) carboxamide, morpholinyl, piperidinyl, O—M, CH2—(CH2)q—M, O—(CH2)q—M, (CH2)q—O—M, and CH═CH—M;
- wherein R5 and R6 are independently selected from the group consisting of hydrogen, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, benzyl or R5 and R6 are taken together to form a 5-7 membered heterocyclic ring;
- M is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, 2-methylthioazoyl, thiazoyl, 2-thienyl, 3-thienyl, 4-thienyl and pyrimidyl;
- and
- q is 0-2;
- J and K are taken together with the nitrogen and carbon atoms to which they are bound to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from O, S, SO or SO2;
- X is selected from the group consisting of Ar, —OR2, and —N(R3)R4;
- wherein R2 has the same definition as R1;
- R3 and R4 independently have the same definitions as B and D;
- or R3 and R4 are taken together to form a 5-7 membered heterocyclic aliphatic or aromatic ring;
- and
- m is 0 or 1;
- b) a neurotropic factor;
- and
- c) a pharmaceutically suitable carrier.
21 more elements
A pharmaceutically acceptable composition comprising:
- a) a neurotrophic amount of a compound of formula (II):
- wherein:
- J and K are taken together with the nitrogen and carbon atoms to which they are bound to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from O, S, SO or SO2;
- wherein each Ar is independently selected from phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyraxolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isotriazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl;
- and
- wherein each Ar is optionally and independently substituted with one to three substituents independently selected from hydrogen, halogen, hydroxyl, nitro, —SO3H, trifluoromethyl, trifluoromethoxy, (C1-C6) straight or branched alkyl, O—((C1-C6) straight or branched alkyl), O-benzyl, O-phenyl, 1,2-methylenedioxy,—NR5R6, carboxyl, N—(C1-C6 straight or branched alkyl or C3-C5 straight or branched alkenyl) carboxamide, N,N-di-((C1-C6) straight or branched alkyl or (C3-C5) straight or branched alkenyl) carboxamide, morpholinyl, piperidinyl, O—M, CH2—(CH2)q—M, O—(CH2)q—M, (CH2)q—O—M, and CH═CH—M;
- wherein R5 and R6 are independently selected from the group consisting of hydrogen, (C1-C6) straight or branched alkyl, (C2-C6) straight or branched alkenyl or alkynyl, benzyl or R5 and R6 are taken together to form a 5-7 membered heterocyclic ring;
- M is selected from the group consisting of 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, 2-methylthioazoyl, thiazoyl, 2-thienyl, 3-thienyl, 4-thienyl and pyrimidyl;
- q is 0-2;
- and
- w is 1 or 2;
- b) a neurotrophic factor;
- and
- c) a pharmaceutically suitable carrier.
11 more elements
Dependencies are inferred from the claim text.